The increasing popularity and widespread use of cocaine has reached epidemic proportions. Accompanying the increase in cocaine abuse has been an escalation in the number of cocaine related emergency room visits, hospital admissions and deaths. Indeed, there is increasing evidence that cocaine can provoke lethal cardiovascular events including stroke, myocardial infarction, and malignant cardiac rhythm disorders such as ventricular fibrillation (VF). In spite of the growing association between lethal cardiac events, relatively little is known about the mechanisms precipitating these cardiovascular event, particularly VF. It is well established that cocaine can enhance the effects of adrenergic stimuli which are, in turn, known to reduce cardiac electrical stability. The mechanism by which enhanced adrenergic activity contributes to VF is not known. Ultimately activation of adrenergic receptors must evoke a variety of cellular responses in the cardiac tissue. These alterations within the cardiac cells could contribute significantly to the development of VF. It is therefore the purpose of the proposed series of experiments to: a) investigate the effects of cocaine on cardiac electrical stability; b) determine the role that cocaine-induced increases in adrenergic activity play in VF; c) determine the role that intracellular mediators of cocaine play in VF; and d) investigate the hemodynamic effects of cocaine with particular emphasis enhancement of adrenergic activity leads to the accumulation of cytosolic calcium, and thereby increases the susceptibility to VF, will be tested. The effects of chronic cocaine use and acute withdrawal on the sensitivity to VF will also be investigated. The combination of exercise, acute ischemia and cocaine has been shown to induce VF reliably and will serve an a model of cocaine-induced VF. Pharmacologic interventions will be used to investigate adrenergic and intracellular contributions to VF. It is anticipated that once the mechanisms responsible for cocaine-induced VF have been determined, novel therapeutic interventions can be devised to reduce the number of these untimely deaths.